Left Ventricular Structural and Functional Abnormalities in Type 2 Diabetes Mellitus

(1)

A DISSERTATION ON

“LEFT VENTRICULAR STRUCTURAL AND

FUNCTIONAL ABNORMALITIES IN TYPE 2

DIABETES MELLITUS”

M.D DEGREE

BRANCH - I

(GENERAL MEDICINE)

MARCH 2007

(2)

CERTIFICATE

This is to certify that the dissertation titled “STUDY OF LEFT

VENTRICULAR

FUNCTIONAL

AND

STRUCTURAL

ABNORMALITIES IN TYPE 2 DIABETES MELLITUS"

submitted by Dr. S.PALANISAMY to the Faculty of General

Medicine, The Tamilnadu Dr. M.G.R. Medical university, Chennai

in partial fulfillment of the requirement for the award of M.D. Degree

Branch I (General Medicine) is a bonafide research work carried out

by him under our direct supervision and guidance.

Dr. A. AYYAPPAN M.D., Dr. NALINI GANESH M.D.,

Professor of Medicine, Professor and Head

Chief II Medical Unit Department of Medicine,

Department of Medicine, Govt. Rajaji Hospital,

Govt. Rajaji Hospital, Madurai Medical College,

Madurai Medical College, Madurai.

(3)

DECLARATION

I, Dr. S. PALANISAMY, solemnly declare that the

dissertation

titled

“STUDY

OF

LEFT

VENTRICULAR

STRUCTURAL AND FUNCTIONAL ABNORMALITIES IN

TYPE-2 DIABETES MELLITUS” has been prepared by me. I also

declare, this bonafide work or a part of this work was not submitted

by me or any other for any award, degree, diploma to any other

university or board either in India or abroad.

This is submitted to The Tamilnadu Dr. M.G.R. Medical

University, Chennai in partial fulfillment of the rules and regulations

for the M.D. Degree Examination in General Medicine to be held in

March 2007.

Place: Madurai Dr.S.PALANISAMY

(4)

ACKNOWLEDGEMENT

My

sincere

thanks

to

The

Dean

,

Dr.S.M.SIVAKUMAR M.S,

for permitting me to use the

facilities of Madurai Medical College and Govt. Rajaji

Hospital to conduct this study.

My Professor and Head of the Department of

Medicine, Prof. NALINI GANESH M.D., has always

guided me, by example and valuable words of advice

throughout the conduct of the study and also during my

postgraduate course. My sincere thanks to her

I will ever remain in gratitude to my chief

Dr.A.AYYAPPAN M.D.,

Department of Medicine, not only

for guiding me through this study, but also for being my

mentor and source of inspiration during the period of my

(5)

My heartfelt thanks to Dr. J. SANGUMANI M.D.,

Dr. L. JERALD MAJELLAH M.D., Dr. P.R. SHEELA

M.D.,

Dr.

S. SOMASUNDARAM

M.D.,

and

Dr.RAMAKRISHNAN M.D. for their valuable support

and guidance throughout the study and also for making

my stay in the unit both informative and pleasurable.

I express my sincere thanks to Dr. ARTHUR

ASIRVATHAM, MD., D.Diab., PROF. AND H.O.D.,

Diab., GRH,Madurai for his guidance throughout the

study.

I express my sincere thanks to Dr. S. MURUGAN

M.D., D.M., Assistant Professor, Department of

(6)

My family and friends have stood by me during my

times of need. Their help and support have been

invaluable to this study.

I would grossly fail in my duty if I fail to mention

here of my patients, who have ungrudgingly borne the

pain and discomfort of the investigations. I cannot but

pray for their speedy recovery and place this study as a

tribute to them and to the numerous others likely

(7)

S.NO.

PAGE

NO.

1.

1. INTRODUCTION

1111

2.

2. AIM OF THE STUDY

3333

3.

3. REVIEW OF LITERATURE

4444

4.

4. MATERIALS AND METHODS

28

5.

5. RESULTS

31

6.

6. STATISTICAL ANALYSIS

44

7.

7. DISCUSSION

46

8.

8. LIMITATIONS

50

9.

9. SUMMARY

51

10.

10. CONCLUSION

52

52 APPENDIX I : BIBLIOGRAPHY

APPENDIX II : GLOSSARY

APPENDIX III : PROFORMA

(8)

INTRODUCTION

The world today is witnessing an epidemic of diabetes

mellitus.1Globally and nationally, diabetes and its complications has become the

most important contemporary and challenging health problem.

It is estimated that there will be more than 200million diabetics

in the world within the next 10 years. India has already become the diabetes

capital of the world with over 30 million affected patients that is alarmingly just

a tip of the iceberg and is expected to touch the 55million mark in 2025.1

The impact of diabetes on both the health of the individual and

the health care system resides almost entirely in the long term complications of

diabetes.

The FRAMINGHAM HEART STUDY revealed marked

increase in peripheral arterial disease, congestive heart failure, coronary artery

disease, myocardial infarction and sudden death(The risk increases from 1 to 5

fold) in diabetics.2

The American Heart Association recently designated DM as a

major risk factor for cardiovascular disease along with other major risk

factors(smoking,hypertension and hyperlipidemia)3

Though DM is associated with a multitude of cardiovascular

complications recent studies have suggested structural myocardial involvement

(9)

relatively early in the course of the disease,15 initially impairing the diastolic

relaxation and when more extensive resulting in decreased myocardial

contraction. Prior to the development of symptomatic CHF sub-clinical LV

dysfunction (systolic and diastolic) does exist for some time.5

Further, increased LV mass has been documented in Type 2

Diabetes even in normotensive individuals at an early stage. LVH is an ominous

prognostic sign and independent risk factor for further cardiac events13 and

hence identification of this subset of patients would enable early interventional

strategies that could decrease the incidence of cardiac events.

There have been few studies that have evaluated the

development of systolic and diastolic LV dysfunction and LV mass in Type 2

DM patients, who are normotensive and have no cardiac symptoms.11

The present study was undertaken to make further inroads into

this aspect of diabetes that would have far flung implications in management of

(10)

AIM OF THE STUDY

Echocardiographic assessment of left ventricular functional and structural

abnormalities in Type 2 DM patients who are normotensive and without

any cardiac symptoms.

To assess the relationship between the duration of diabetes mellitus and

(11)

REVIEW OF LITERATURE

Definition:

DIABETES MELLITUS is defined as a syndrome characterized by

chronic hyperglycemia, associated with disturbances of carbohydrate, fat and

protein metabolism due to absolute or relative deficiency in insulin secretion

and/or action.

In view of the wide heterogeneity, Diabetes is regarded as a “syndrome”

rather than a disease entity.1

Classification:

This classification is based on the pathogenic process that leads to

hyperglycemia as opposed to earlier criteria that included the age of onset and

type of therapy.3

The classification of DM:

1. Type 1 DM (β cell destruction, usually leading to absolute insulin

deficiency)

A: Autoimmune mediated

(12)

2. Type 2 DM (may range from predominantly insulin resistance with

relative insulin deficiency to a predominantly insulin secretory defect

with insulin resistance)

3. Other types:

Genetic defects of β cell function characterized by mutation in:

1. Hepatocyte nuclear transcription (HNF) 4α MODY 1

2. Glucokinase MODY2

3. HNF-1α MODY3

4. Insulin promoter Factor (IPF) 1 MODY4

5. HNF-1β MODY5

Genetic defects in insulin action

1. Type A insulin resistance

2. Leprechaunism

3. Lipoatrophic diabetes

Disease of the exocrine pancreas

Endocrinopathies

Drugs, Toxin induced

Infections

Other genetic syndromes

(13)

TYPE 1 DIABETES MELLITUS:

This was previously known as Insulin Dependent Diabetes Mellitus

(IDDM). These patients require insulin for survival, as the endogenous insulin

secretion is almost absent in them. This disease has its onset most often in

childhood and adolescence, although it may occur at any age. Though usually

abrupt in onset, it can be protracted in its course. Genetic factors, autoimmunity

and environmental factors play a major role in the causation and the

precipitation of Type1 diabetes.

The auto immune aetiology of the disorder is well recognized by the

presence of immune markers, like Islet cell antibodies (ICA), Insulin

autoantibodies and antibodies against 64KD antigen.

Type 1 DM comprises of two broad categories, Type 1A and Type 1B.

Type 1A diabetes results from autoimmune beta cell destruction, which usually

leads to insulin deficiency. Type1B diabetes is characterized by insulin

deficiency of unknown aetiology, with lack of immunological markers

indicative of autoimmune destructive process of β cell.

Pathogenesis:

Type 1 DM develops as a result of synergetic effect of genetic,

environmental and immunological factors that ultimately destroy the β cells.

Individuals with a genetic susceptibility have normal cell β cell mass at birth,

(14)

months to years. The autoimmune process is thought to be triggered by an

infectious or environmental stimulus and to be sustained by a beta cell specific

molecule. In the majority of the individuals immunological markers appear

after the triggering event, but before diabetes become clinically overt. β cell

mass then begins to decline and insulin secretion becomes progressively

impaired, although normal glucose tolerance is maintained. Features of diabetes

do not become evident until a majority (>80%) of β cells are destroyed. At this

point, the residual functional β cells still exist, but are insufficient in number to

maintain glucose tolerance. The events that contribute to the transition from

glucose intolerance to frank diabetes are associated with increased insulin

requirements, as might occur during infections or puberty.

Various factors can be attributed to the pathogenesis of Type 1 DM: 1. Genetic factors

Genetic contribution to Type 1DM involves multiple genes. The

concordance of Type 1DM in identical twins is between 30-70%3, indicating

that additional modifying factors must be involved in determining whether

diabetes develops or not. The major susceptibility gene for Type1DM is located

in HLA region on chromosome 6. Most individuals with Type 1 DM have HLA

DR3/DR4 halotype. Refinements in genotyping of HLA loci have shown that

the halotypes DQA1*0301, DQB1*0302, DQA1*501 and DQB1*0201 have

(15)

2. Autoimmune factors:

Pathologically, the pancreatic islets are infiltrated with

lymphocytes (in a process termed insulitis) due to autoimmunity, leading to

destruction of the β cells. As a result, the following abnormalities appear in the

immune system;

a. Islet cell autoantibodies

b. Activated lymphocytes in the islets, peripancreatic lymphnodes and

the systemic circulation.

c. T lymphocytes that proliferate when stimulated with islet proteins,

and

d. Release of cytokines within the insulitis.

3. Immunological markers:

Islet cell autoantibodies are present in the majority (75%) of individuals

diagnosed as Type 1DM.This includes antibodies to GAD (Glutamic acid

decarboxylase) 65, IA-2/ICA-512 and Islet gangliosides.

4. Environmental factors:

Various environmental factors have been proposed to trigger the

autoimmunity in genetically susceptible individuals. They are mainly viral

infections (Coxsackie and Rubella), early exposure to bovine milk proteins and

(16)

TYPE 2 DIABETES MELLITUS

Type 2 DM is a heterogenous disorder with a complex aetiology that

develops in response to genetic and environmental influences. Central to the

development of Type 2 DM are Insulin resistance and Abnormal insulin

secretion. Although controversy remains regarding the primary defect, most

studies support the view that insulin resistance precedes insulin secretory

defects.

Genetic considerations:

Although the major genes that predispose to this disorder

have yet to be identified it is clear that the disease is polygenic and

multifactorial. The concordance of Type 2 DM in identical twins is between

70-90%3. If both parents have Type2DM the offspring have risk approaching 40%.

Pathogenesis:

Type 2 DM is characterized by 3 pathophysiological abnormalities:

1. Peripheral insulin resistance

2. Impaired insulin secretion

and 3. Excessive hepatic glucose production

Peripheral insulin resistance:

In early stages glucose tolerance remains normal despite insulin

resistance as the pancreatic β cells compensate by increased insulin output.

However as the insulin resistance and compensatory hyperinsulinemia progress,

(17)

hyperinsulinemic state. Thus begins a spectrum from impaired glucose tolerance

to overt diabetes mellitus reflecting the progress towards β cell failure.

Insulin resistance results from a combination of genetic susceptibility and

obesity. Insulin resistance impairs glucose utilization by insulin sensitive tissues

and increases hepatic glucose output, both effects contribute to hyperglycemia.

Increased hepatic glucose output and decreased peripheral glucose utilization

account for the increased fasting plasma glucose levels and postprandial

hyperglycemia respectively. The molecular mechanism of postreceptor defects

include (a). Polymorphism in IRS-1 (b)PI-3 kinase signaling defects, which

reduces translocation of GLUT4 to the plasma membrane and (c) elevated levels

of free fatty acids in obese individuals results in impaired glucose utilization in

skeletal muscle, promote glucose production by the liver and impair beta cell

(18)

Impaired insulin secretion:

The cause of impaired insulin secretion in type 2 DM is

unclear. It is hypothesized that this may be due to (a) Islet amyloid

polypeptide/amylin. (Amylin has been reported to lower basal and insulin

stimulated glycogen synthetase in the muscle and also to inhibit glucose

stimulated insulin secretion) (b)Glucotoxicity. Chronic hyperglycemia

paradoxically impairs beta cell function. (c) Lipotoxicity. Elevated free fatty

acids and dietary fat worsen islet function.

Increased hepatic glucose production

In type2 DM, insulin resistance in the liver reflects the failure of

hyperinsulinemia to suppress neoglucogenesis which results in fasting

hyperglycemia and decreased glycogen storage by the liver in the postprandial

state.

.

Risk factors for Type 2 DM:

1. Family history of Diabetes.

2. Obesity(BMI≥25kg/m2)

3. Habitual physical inactivity

4. Race/Ethnicity

5. Previously identified IFG or IGT

(19)

7. Hypertension(BP≥140/90mmHg)

8. HDL cholesterol level ≤35mg/dl), or TGL level ≥250mg/dl

9. Polycystic ovary syndrome or Acanthosis nigricans

(20)

Differentiation of Type 1 and Type 2 DM by clinical criteria: 3 S.No Type 1 DM Type 2 DM

1 Onset of disease prior to age of

30yrs

Onset of disease after 30years

2 Lean body habitus 80%obese(elderly individually may be

lean)

3. Requirement of insulin as the

initial therapy

May not require insulin therapy initially

4. Propensity to develop

ketoacidosis

Not usually prone for ketoacidosis

5. Associated with other

autoimmune

disorders(eg.autoimmune

thyroiditis,pernicious anaemia

and vitiligo)

Associated with conditions like

hypertension, dyslipidemia, PCOD and

cardiovascular disease.

6. Presence of ICA and GAD

Antibodies

(21)

DIAGNOSIS:3

Symptoms of Diabetes plus random* blood glucose concentration

>11.1mmol/L(200mg/dl)

or

Fasting** plasma glucose >7mmol/L(126mg/dl)

or

2hr plasma glucose>11.1mmol/L(200mg/dl)

during on oral GTT***.

*Random is defined as without regard to time since the last meal.

** Fasting is defined as no caloric intake for at least 8hrs.

*** The test should be performed using a glucose load containing the equivalent

of 75g anhydrous glucose dissolved in water; not recommended for routine use.

Long term Complications:

Although chronic hyperglycemia is an important aetiologic factor leading

to the complications of DM, four prominent theories have been proposed to

explain how hyperglycemia might lead to the chronic complications:

1. Formation of advanced glycosylation end products (AGEs) via

nonenzymatic glycosylation of intra and extracellular proteins.

2. Increased metabolism of glucose through the sorbitol pathway by the

(22)

osmolality, generates reactive oxygen species and alters the redox

potential and thus leads to cellular dysfunction.

3. Increase the formation of DAG (Diacyl glycerol) leading to activation

of Protein kinase C which in turn alters the transcription of genes for

fibronectin, type-IV collagen, contractile proteins and extracellular

matrix proteins.

4. Increased formation of Fructose-6-phosphate through the Hexosamine

pathway which may alter the function of nitric oxide synthase or by

changes in the gene expression of TGF-β and PAI-1(Plasminogen

(23)

S.No. Chronic complications of DM

1. Macroangiopathy Coronary artery disease, Cerebrovascular disorder,

Peripheral vascular disease

2. Microangiopathy Retinopathy, Macular edema, Nephropathy,

Neuropathy(Sensory, Motor), Autonomic

3. Others Dermatopathy, GIT (gastroparesis,

diarrhea),Genitourinary(Uropathy, sexual

(24)

LV STRUTURAL AND FUNCTIONAL ABNORMALITIES NORMAL LV FUNCTION

The three basic events of the cardiac cycle are

1. LV contraction

2. LV relaxation

3. LV filling.

1. LV Contraction

It comprises of 1.Isovolumic contraction phase extending from closure of

mitral and tricuspid valve to the time when pressures in the left and right

ventricles exceed the pressures in the aorta and the pulmonary artery 2.Phase of

ventricular ejection that begins as the aortic and pulmonary valves open and

ends when the ventricular pressures drop rapidly.

2. LV Relaxation

It comprises of i). Protodiastole (Phase of reduced ejection) the period

when the ventricular pressures drop very rapidly and ends when the

momentum of ejected blood is overcome and aortic and pulmonary valve close.

ii). Isovolumic ventricular relaxation: Begins with closure of the aortic and

pulmonary valve and ends with the opening of AV valves as ventricular

(25)

3. Left ventricular filling:

It comprises 1.Rapid filling phase which starts as pressure in the ventricle

drops below the left atrial pressure and the mitral valves open. This period of

rapid filling ends when pressure in the atrium and ventricle equalize. 2.

Diastasis: virtually no flow into the ventricle is seen during this phase 3.Atrial

systole (Late diastolic phase).

LV SYSTOLIC FUNCTION: 6

The determinants of LV systolic function are 1.preload 2.afterload

3.myocardial contractility and 4.heart rate

The specific indices used to evaluate LV systolic function are:

1. Ejection fraction

Ejection fraction is defined as the ratio of the stroke volume to end

diastolic volume.

EF = EDV – ESV/EDV × 100(%)

The normal value of LVEF is 55-75%.

2. End systolic ventricular volume/dimension:

ESV is strongly afterload dependent and is relatively independent of

preload. It is useful to assess LV function in patients with valvar regurgitation.

3. Other indices:

Include VCF (Velocity of circumferential fibre) shortening, Afterload

(26)

stiffness, Preload recruitable stroke work and the Maximum rate of pressure

rise.

LV DIASTOLIC FUNCTION6

Assessment of cardiac performance has traditionally focused on

systolic function. More recently however diastolic function has been found to

play an important role in cardiac morbidity and mortality. Diastolic function is

influenced importantly by ventricular structure and composition. However,

clinically, four phases of diastolic function need to be distinguished

1.isovolumetric relaxation 2.early rapid diastolic filling (E) 3.slow ventricular

filling (Diastasis) and 4. late atrial filling (A).

Diastolic function is influenced by several factors which include

1.myocardial relaxation 2.ventricular filling 3.elastic recoil 4.heart rate and

(27)

Specific indices used to evaluate diastolic dysfunction include:

1. IVRT (Intraventricular isovolumetric relaxation time):

This is the interval from the aortic valve closure to mitral valve opening.

Normal: 70-90millisecond

2. Peak mitral flow velocity

Peak mitral flow velocity of early rapid filling wave (E) and Peak

velocity of late filling wave (A) due to atrial contraction are expressed as E/A

ratio. Normal >1.

3. Deceleration time (DT):

This is the interval from the peak of the E velocity to extrapolation to

baseline. Normal <240ms.

4. Other indices include:

Pulmonary vein flow velocities, tricuspid flow velocities and hepatic vein

flow velocities and SVC flow velocities.

(28)

A E A I V R T I V C T Aortic Outflow

NORMAL DIASOLIC FILLING PATTERN

The rate of myocardial relaxation and compliance change with aging, so

that, different diastolic filling patterns are expected for different age groups.

Abnormalities of LV systolic function:

This is usually identified on echocardiograhic measurement of Ejection

Fraction. EF <55% denotes LV dysfunction.

Abnormalities of LV diastolic function: 6 1. Diastolic abnormalities:

Characterized by abnormal filling indices, they are commonly identified

on echo by prolonged IVRT, however, these patients have no clinical

symptoms. In this situation the ventricle is able to compensate for abnormal

diastolic function and to maintain a normal level of left ventricular filling

pressure. E

AT DT

(29)

2. Diastolic dysfunction:

Characterized by increased diastolic filling pressure which may be

responsible for the occurrence of dysnoea especially during exercise.

3. Diastolic heart failure:

Associated with clinical signs like PND and orthopnoea.

Echocardiographic classification of diastolic filling27

DT (msec) IVRT (msec) MITRAL E/A PVS2&PVd

Normal 160-240 70-90 1-2 PVS2≥PVd

Impaired

Relaxation

>240 >90 <1 PVS2>>PVd

Pseudo

normal

160-200 <90 1-1.5 PVS2<PVd

Restrictive

filling

<160 <90 >1.5 PVS2<<PVd

The clinical differentiation of the two forms of heart failure is of utmost

(30)

LEFT VENTRICULAR MASS

The role of LV mass estimation and diagnosis of LVH in cardiovascular

disease management is based on epidemiological research and clinical grounds.

In general, heart size increases during infancy and adolescence due to body size

enlargement, and at this stage, the gender difference becomes prominent. The

physiological factors8 that contribute to LV mass are:

1. Gender-women have increased parietal hypertrophy response to

pressure than men.

2. Ethnicity-some ethnic groups have higher LV mass(African

Americans)

3. Obesity

4. Age: LV mass progressively increases with age, particularly parietal

thickness. However, Dannenberg and coworkers demonstrated that LV mass

did not increase with age in a healthy sub-sample of the Framingham study,

suggesting that most of the supposed physiological increase is caused by other

determinants that include Hypertension, DM with metabolic syndrome, Alcohol

consumption, Increased salt intake, Smoking and Increased leisure time physical

activity in men, Blood lipid, Pulmonary function and Heart rate.

Echocardiographic measurement of LV mass is generally calculated

as the difference between the epicardium delimited volume and the LV chamber

(31)

imaging can be employed to calculate LV mass. Despite more than 30 years of

use Echocardiograph based LV mass calculation and definition are still variable

among Ultrasound technicians around the world. The Echocardiographic

criteria to calculate LV mass in this study was: 18

(RWT) (LVMI)g/m2

Normal <0.45 <131(men), <100(women)

Concentric

Remodeling >=0.45

<131(males), <100(females)

Concentric

Hypertrophy

>=0.45 >131(males), >100(Females)

Eccentric

Hypertrophy

(32)

DIABETES AND CARDIOVASCULAR DISEASE

Diabetes mellitus is an independent risk factor for cardiovascular disease

(CVD). In the FRAMINGHAM STUDY the risk of CVD for diabetic

subjects at baseline was two fold higher in men and three to four fold for

women after adjustment for other risk factors such as dyslipidemia and

hypertension. More recently NHANES1 study also showed that the diabetic

population was twice as likely to develop CAD as the nondiabetic population

with excess mortality .

The MRFIT STUDY shows that men with diabetes had an absolute risk

of death due to CAD more than three times than the nondiabetic cohort.

In the six nation OASIS study6, diabetic patients presenting with

unstable angina or Non Q MI had increased rate of stroke, CHF and death

during index hospitalization compared with the non-diabetic group.

In the Finnish contribution to WHO MONICA (World Health

Organization Multinational Monitoring of Trends and Determinants of

Cardiovascular Disease) project, the 1 year mortality was 38% higher for

diabetic men and 86% higher for women.

In view of the above, studies have been undertaken in recent times to

identify structural and functional abnormalities in normotensive diabetics who

have no cardiac symptoms. Most of the recent studies identified changes in LV

mass and LV systolic and diastolic function indices even before the patients are

(33)

The main factors that contribute to the increased incidence of cardiovascular disease in DM are: 1

1. The acceleration of atherosclerotic process leading to

macrovascular disease.

2. Development of specific cardiomyopathy

3. Progressive microvascular disease

4. Development of autonomic neuropathy

Noninvasive methods have confirmed that fibrosis is a key feature of the

heart of diabetic patients without evident cardiac disease. Increased level of

collagen in diabetics have been associated with changes in left ventricular

diastolic function.11 Chronic hyperglycemia leads to the formation of AGE’s

that modify the extracellular matrix, resulting in inelasticity of the vessel wall

and could interfere with myocardial function as well.6 These coupled with

abnormal myocardial calcium handling result in poor elastic recoil, leading to

impairment in early rapid diastolic filling(E) manifest by prolonged IVRT and

DT, and increased Mitral (A) velocity.

In the setting of insulin resistance, there is release of free fatty acids from

adipose tissue into the plasma. FFA becomes the dominant fuel for myocardial

energy in the form of free fatty acid oxidation within cardiac myocytes. In

(34)

glucose oxidation in these cells. Free fatty acid oxidation is a less efficient

means of generating adenosine triphosphate than glucose oxidation thus

contributing to chronic left ventricular dysfunction.

The impact of glucose intolerance and insulin resistance on cardiac

structure and function is as follows:

(35)

MATERIALS AND METHODS

All patients included in the study were taken from the Diabetology

department of Govt. Rajaji Hospital, Madurai.

This is a case control cross sectional study. The study period was from

August –2005 July 2006. The diagnosis of the cases was based on clinical

features and WHO criteria for DM. The total number of patients in the study

group were 60, this includes 28 males and 32 females. The study group was

further subdivided into three groups based on the duration of Diabetes.

GROUP I: 0-5YEARS

GROUP II: 6-10YEARS

GROUP III: >10YEARS

The control group was taken from the Outpatient Dept of Medicine and

Inpatients admitted for other ailments. This group was designated as GROUP

IV. Total number of controls was 40, which included 20 males and 20 females.

All cases and controls were within the age of 40-60 years. Both cases and

controls were examined and recruited in the study in the same time period. All

subjects gave informed consent for their participation in the study.

Inclusion criteria:

1. All cases of Type 2DM diagnosed by WHO criteria

2. Age: 40-60 years

3. BP: <130/85 (at least 3 recordings with the highest recording

(36)

Exclusion criteria were

1. Systemic Hypertension(BP>140/90)

2. Ishaemic heart disease(abnormal E.C.G. and RWMA on

Echo)

3. CHF

4. Congenital or Acquired Valvular Heart Disease

5. CRF

6. Age>60yrs

7. cardiac signs and symptoms(exertional dysnoea, chest pain,

palpitation, raised JVP)

8. PDR/NPDR and

9. Microalbuminuria.

Echocardiography:

Patients were evaluated by 2D and Doppler Echocardiography. All

examinations were performed using a ALOKA SSD 2000 machine 2.5Mhz

(37)

1.Ejection Fraction2.LV mass 3.Mitral Early filling velocity (E), Mitral

late atrial filling velocity (A),E/A was then derived 4.IVRT

and 5.DT.

Operators blinded to the diabetes diagnosis of the patients performed all

Echocardiographic measurements.

Computer Analysis of data was done using the software epidemiological

information package – 2002 developed by Centre for Disease Control and

Prevention, Atlanta in collaboration with WHO.

(38)

[image:38.595.67.528.313.583.2]

A. Comparison of Parameters in Diabetic Group (cases) and non diabetic group (Cantnoes)

Table 1: AGE

Diabetic Non-Diabetic Age Group

No % No %

40 – 44 14 23.3 10 25

45 – 49 14 23.3 9 22.5

50 – 54 9 15 9 22.5

55 – 59 14 23.3 8 20

60 & above 9 15 4 10

Total 60 100 40 100

Mean 50.25 50.45

S.D. 6.95 6.06

(39)

[image:39.595.68.533.151.277.2]

Table 2: SEX

Diabetic Non-Diabetic Sex

No % No %

Male 28 46.7 20 50

Female 32 53.3 20 50

p 0.9024 (Not Significant)

Table 3: EF %

Diabetic Non-Diabetic EF%

No % No %

Normal 46 76.7 36 90

Abnormal 14 23.3 4 10

Mean 60.56 63.82

S.D. 7.53 7.18

[image:39.595.63.531.400.578.2]

(40)

[image:40.595.65.531.309.487.2]

Table 4: LV Mass (gm/m2)

Diabetic Non-Diabetic LV Mass (gm/m2)

No % No %

Normal 39 65 34 85

Abnormal 21 35 6 15

Mean 98.77 97.59

S.D. 24.65 8.45

(41)

[image:41.595.66.531.149.341.2]

Table 5: Deceleration Time

Diabetic Non-Diabetic Deceleration Time

No % No %

Normal 34 56.7 28 70

Abnormal 26 43.3 12 30

Mean 205.65 207.6

S.D. 43.74 32.1

[image:41.595.65.534.280.616.2]

Table 6: IVRT

Diabetic Non-Diabetic IVRT

No % No %

Normal 21 35 22 55

Abnormal 39 65 18 45

Mean 101.65 93.2

S.D. 25.8 17.5

(42)

Table 7: E/A Ratio

Diabetic Non-Diabetic E/A Ratio

No % No %

Normal 25 41.7 28 70

Abnormal 35 58.3 12 30

Mean 0.94 1.15

S.D. 0.28 0.23

[image:42.595.66.531.310.486.2]

(43)

[image:43.595.68.530.327.502.2]

Table 8: Pulse Rate per Minute

Diabetic Non-Diabetic Pulse Rate

No % No %

Normal 46 76.7 40 100

Abnormal 14 23.3 - -

Mean 90.55 81.7

S.D. 12.65 5.52

(44)

B. Comparison of Parameters within Diabetic Group according to duration of diabetics – I) 1 to 5 years II) 6-10 years III) More than 10 years

[image:44.595.66.531.142.473.2]

Table 9: AGE

I II III

Age Group

No % No % No %

40 – 44 5 25 6 30 3 15

45 – 49 4 20 5 25 5 25

50 – 54 2 10 3 15 4 20

55 – 59 7 35 3 15 4 20

60 & above 2 10 3 15 4 20

Total 20 100 20 100 20 100

Mean 50.5 48.7 51.9

S.D. 7.4 7.1 6.3

p 0.5218

Table 10: Sex and Duration if Diabetes

I II III

Sex

No % No % No %

Male 9 45 9 45 10 50

Female 11 55 11 55 10 50

‘p’ Value Between

I & II - 0.7506 (Not Significant)

I & III - 1.000 (Not Significant)

(45)

[image:45.595.67.530.325.481.2]

Table 11: EF% and duration of Diabetes

I II III

EF%

No % No % No %

Normal 18 90 15 75 13 65

Abnormal 2 10 5 25 7 35

Mean 60.42 62.7 58.6

S.D. 6.1 9.6 6.2

(46)

[image:46.595.64.533.263.436.2]

Table 12: LV Mass (gm/m2) and duration of Diabetes

I II III

LV Mass

No % No % No %

Normal 17 85 13 65 9 45

Abnormal 3 15 7 35 11 55

Mean 86.5 98.8 111.0

S.D. 19.7 30.2 16.5

I & III - 0.0203 (Significant)

(47)

[image:47.595.62.533.91.760.2]

Table 13: Deceleration Time and duration of Diabetes

I II III

Deceleration

Time No % No % No %

Normal 12 60 11 55 11 55

Abnormal 8 40 9 45 9 45

Mean 192.8 212.0 212.2

S.D. 48.7 49.5 39.7

[image:47.595.64.534.96.279.2]

II & III - 0.7506 (Not Significant)

Table 14: IVRT and duration of Diabetes

I II III

EF%

No % No % No %

Normal 6 30 7 35 8 40

Abnormal 14 70 13 65 12 60

Mean 108.1 99.5 97.4

S.D. 20.4 31.3 24.6

(48)

Table 15: E/A Ratio and duration of Diabetes

I II III

E/A Ratio

No % No % No %

Normal 10 50 8 40 7 35

Abnormal 10 50 12 60 13 65

Mean 1.0 0.94 0.88

S.D. 0.3 0.29 0.27

[image:48.595.61.531.112.426.2]

II & III - 1.00 (Not Significant)

Table 16: Pulse Rate per minute and duration of Diabetes

I II III

Pulse Rate

No % No % No %

Normal 16 80 16 80 14 70

Abnormal 4 20 4 20 6 30

Mean 88.2 89.4 94.1

S.D. 12.1 13.2 12.4

[image:48.595.67.529.126.275.2]

(49)

[image:49.595.67.531.337.511.2]

C. Comparison of parameters within the study group(diabetics) according to Sex

Table 17: Relationship between sex and LV mass

Male Female

LV Mass

No % No %

Normal 24 85.7 15 46.9

Abnormal 4 14.3 17 53.1

Mean 97.88 99.54

S.D. 26 23.79

(50)

[image:50.595.66.493.411.582.2]

Table 18: Relationship between sex and E/A ratio

Male Female

E/A

No % No %

Normal 13 46.4 12 37.5

Abnormal 15 53.6 20 62.5

Mean 0.948 0.9365

S.D. 0.303 0.272

Table19: Relationship between sex and pulse rate

Male Female Pulse Rate

No % No %

Normal 25 89.3 21 65.6

Abnormal 3 10.7 11 34.4

Mean 85.5 95.0

S.D. 11.76 11.88

(51)

STATISTICAL ANALYSES

This study was a cross sectional case control study conducted in 60 cases

of Type2 DM who satisfied inclusion criteria and 40 age and sex matched

controls. The mean age of cases was 50.25 years and controls 50.45years.

Of the 60 cases 28(46%) were males and 32(53.3%) were females. Of the 40

controls, 20 were males and 20 were females.

The cases were divided into three groups based on the duration of

diabetes. Group I comprising those with diabetes of 0-5 yr duration while

Groups II and III comprising those with duration of 5-10yrs and >10yrs

respectively. The number of cases in each group was 20.

The mean age of Group I patients was 50.5yrs. Of the 20 patients in the

Group,9 were males and 11 were females.

The mean age of Group II patients was 48.7yrs. Of the 20 patients in the

Group, 9 were males and 11 were females.

The mean age of Group III patients was 51.7yrs. Of the 20 patients in the

group, 10 were males and 10 were females.

In this study, regarding EF <55% considered to be systolic dysfunction.

E/A ratio <1, IVRT >90msec and DT >240msec taken as an abnormal diastolic

dysfunction.

Regarding LV Mass male >131gm/m2 and female >101gm/m2 taken as an

(52)

Observations of EF revealed that abnormalities were present in 10% of

Group I, 25% of Group II and 35% of Group III while only 10% of the control

group(Group IV) showed abnormalities.

Observations of LV mass revealed that abnormalities were present in

15% of Group I, 35% of Group II and 55% of Group III while only 15% of the

control group(Group IV) showed abnormalities.

Observations of DT revealed that abnormalities were present in 40% of

Group I, 45% of Group II and 45% of Group III while 30% of the control group

(Group IV) showed abnormalities.

Observations of IVRT revealed that abnormalities were present in 75% of

Group I, 65% of Group II and 60% of Group III while 45% of the control group

(Group IV) showed abnormalities.

Analysis of E/A ratios revealed that abnormalities were present in 50% of

Group I, 60% of Group II and 65% of Group III. 30% of GroupIV (controls)

also revealed abnormalities.

It was observed that a resting pulse rate >100 was observed in 20% of

Group I and II and 30% of Group III cases while the pulse rate was within the

(53)

DISCUSSION

In the study, it was observed that 35% of diabetics (cases) and 15% of

non-diabetics (controls) had increased LV mass, (‘p’ < 0.045) which is

statistically significant. This is in conformity with other studies as shown below.

Studies by Hirayama et al 13 observed the increased incidence of LV

mass among diabetics (normotensive and asymptomatic) than non-di abetics.

Dawson et al11 observed that the prevalence of LVmass abnormalities was 71%

among diabetics compared to 35% in our study, this may be due to non

exclusion of hypertensives in the study. Nielsen et al16 observed that increased

LV mass was found in 51% of diabetics.

Intragroup analyses of cases revealed that Increased LV mass was seen

in 15% of Group I, 35% of Group II and 55% of Group III. There was

statistically significant association between Group I and Group III (P < .0203).

This indicates that the development of increased LV mass is dependent on the

duration of Diabetes.

With regard to EF, 23.3% of diabetics and 10% of non diabetics had

(54)

in conformance with other studies Hiroyoshima et al, Siwach et al4, Saner et al19. However studies by Annonu et al14 observed that diabetics had low EF, however the study group included the presence of complications of diabetes

which were excluded in our study. Further Oirko et al15 also observed low EF

in diabetics. Thus studies regarding EF abnormalities in DM have observed

varying results which need to be further investigated.

Observations of IVRT revealed that 65% of cases and 45% of controls

show abnormalities. However this was not statistically significant.( (p<0.0762)

Observations of DT revealed that 43.3% of cases and 30% of controls

show abnormalities which was found to be statistically significant.(p <0.2561)

Observations of E/A ratio revealed that 58.3% of cases (diabetics) and

30% of controls showed abnormalities, which was found to be statistically

significant. (p<0.0099).

The observations on IVRT,DT and E/A ratio are in conformance with the

study by Siwach et al. wherein 68% of diabetics had E/A <1 compared to

58.3% in our study Most other studies performed to analyse diastolic function

abnormalities have taken into account E/A ratio as the single parameter of

diastolic function. Spiro Qirko et al, and Elizi et al12 observed values of E/A<1

(55)

relation to the controls. This infers that E/A ratio abnormality is an indicator of

diastolic dysfunction in diabetics. However the reason for the statistically

insignificant values of DT and IVRT abnormalities in diabetics are not known.

Diastolic function abnormalities occur early in the course of disease. This is

evident by the comparison of E/A ratios in Group I and Group III. Which

shows 50% of Group I and 65% of Group III had E/A<1 that was statistically

insignificant. (p<0.5223).Bonitio et al20 and Spiro Qirko et al also observed

the same in their studies.

Interestingly, observations of our study revealed increased resting pulse

rate in diabetics that was subject to statistical analysis. It was observed that

23.3% of cases (diabetics) and none of controls had increased resting pulse rate

which was statistically significant.(p<0.0027). This was earlier documented by

studies by Atheros et al17 and Saner et al. The increase in resting pulse rate is

probably due to diabetic autonomic neuropathy that was not excluded in our

study.

Further observations of LV mass between males and females revealed

that 14.3% of diabetic males and 53.1% of diabetic females had increased LV

mass which was statistically significant. (p,0.004). This reflects the increased

(four fold) cardiovascular mortality in diabetic females compared to males (two

(56)

The occurrence of structural and functional abnormalities in Type 2 DM

as observed in our study clearly state the importance of Echocardiographic

assessment(screening) of all Type 2 DM patients even in the absence of cardiac

(57)

LIMITATIONS

1. The study was restricted to hospital patients, so its relevance to the

general population is unknown.

2. Patients with DM usually have silent ischemia and this factor was not

taken into account in the study.

3. The study is subject to measurement error, subject error and instrument

error, though carefully designed.

4. Ambulatory BP could not be done this may affect the study group to some

extent.

5. Smoking, obesity and dyslipidemia were not excluded from the study

group, this may have some influence on LV mass 9.

(58)

SUMMARY

Echocardiographic assessment of diabetic non-diabetic group revealed the following findings:

1. In diabetic, systolic function not significantly affected when compare to

non-diabetic.

2. Diabetic have increase LV Mass than non-diabetic.

3. In diabetes, females have increase LV Mass than male.

4. The development of LV Mass in diabetic depend upon the duration of

illness.

5. IVRT, DT not significantly affected in diabetic when compare to diabetic.

6. E/A ratio significantly affected between diabetic & non-diabetic.

7. In diabetes, IVRT, DT & E/A ratio not significantly affected according to

the duration of illness.

(59)

CONCLUSIONS

Echocardiographic observation of Type 2 DM patients who are

normotensive and have no cardiac symptoms revealed:

Increased LV mass compared to controls, that is well correlated

with the duration of diabetes and with a female preponderance

LV diastolic dysfunction compared to controls, which does not

correlate with the duration of diabetes mellitus, reflecting the

occurrence of dysfunction early in the course of disease.

LV systolic function analyzed through EF is not significantly

(60)

BIBLIOGRAPHY

1. A.P.I. Textbook of Medicine,6th edition.

2. Plouin IF. The importance of Diabetes as a Cardiovasuclar risk factor.Int

J.Clinic Pract.Suppl 2000(110):3-8.

3. Harrisons Principles of Internal Medicine,16th edition.

4. JIACM 2002;3(2):164-8 Echocardiographic Doppler assessment of cardiac

function in patients of Type 2 DM

5. Ethn Dis 2005. Autumn;15(4)635-40, LV dysfunction in Type 2 DM

without Cardiac symptoms.

6. Braunwald’s Heart Disease A Text Book of Cardiovascular Medicine,7th

edition.

7. Hurst Volume2,10th edition;2019

8. Joslins Diabetes Mellitus,14th edition 989

9. Echocardiographic based LV mass estimation, Murilo Foppa et al.

Cardiovascular Ultrasound 2005,3:17

10. LV function in Type 2 DM in patients without Cardiac symptoms in Zaria,

David SO et al.

11. Epidemiology of LVH in Type 2 DM, Dawson A et al. Diabetolgia 2005

Oct;48(10)

12. Reduced LV diastolic function in asymptomatic patients with Type 2 DM,

(61)

13. Determination of LVmass by echocardiography in normotensive Diabetic

patients. Hirayama et al. PMID11194283

14. LV systolic and diastolic functional abnormalities in asymptomatic patients

with Type 2 DM, Annonu AK et al.PMID 11547274

15. Type 2 DM as an independent predictor of asymptomatic LV diastolic

dysfunction, Spiro Qirko et al, Clinical Science 2005;46(2)225-231

16. LVH in Type 2 DM patients with and without Diabetic nephropathy,

Nielsen et al. PMID 11547254

17. LV systolic and diastolic function in normotensive Type1 diabetic patients

with or without autonomic neuropathy, Athyros et al. PMID12832295

18. Feigenbaumis manual of Echocardiography.6th edition,149

19. Saner H et al. No evidence for systolic and diastolic dysfunction in selected

patients with long term Type 1 DM, PMID 10937927

20. Di Bonito et al. Diastolic dysfunction in patients with Type 2DM of short

duration.

21. Poirier et al. Diastolic dysfunction in normotensive men with well

controlled Type 2 DM.

22. Anderson et al. Prevalence of dysfunction in normotensive men with well

controlled Type 2 DM.AMJ. Cardiol.2001:87;320-323

23. Vanninen et al. A study of diastolic dysfunction in Type 2 DM

24. Sampson et al. Association between LVH and erythrocyte sodium lithium

exchange in normotensive subjects with and without Type 2 DM,

Diabetolgia 1995; 38;454-460

(62)

26. Ohya et al. Hyperinsulinemia and LV geometry in worksite population in

Japan.Hypertension 1996;27;729-734

27. The Echo manual JAE. K.OH., 2nd Edition

28. Nielsen FS, et al; Beneficial impact of ramipril on left ventricular

hypertrophy in normotensive nonalbuminuric Type2 DM patients. Diabetes

Care 1998; 21; 804-809

29. DeMaria, et al; Doppler echocardiographic evaluation of diastiolic

dysfunction. Cliculation.1991; 84(3 Suppl); 1288-95

30. Williams et al; Fasting insulin and left ventricular mass in hypertensives

(63)

TARGET ORGAN ABNORMALITIES IN TYPE 2 DIABETES MELLITUS

Name : Sl. No :

Age : IP.No :

Sex : OP.No :

Duration of Diabetes:

Complaints

General Examination

Investigations

Giddiness

Pallor

Urine Albumin

Palpitation

Jaundice

Hb

Breathlessness

Cyanosis

ESR

Chest discomfort

Clubbing

Blood Sugar

Headache

LNE

Urea

Vertigo

Pedal oedema

Sr. Creatinine

Weakness

Pulse rate /min

Sr. Cholesterol

Dec. in work

performance

Peripheral pulse

ECG

Swelling of Legs

BP Rt UL -mmHg

HR

Bleeding Nose

Lt UL -mmHg

PR

Seizures

Rt LL -mmHg

QRS QT

Sexual

Dysfunction

CVS

AXIS

Others

Apical Impulse

ST- T Segment

JVP

Q Waves

Personal History

Precardium Pulsations

Smoker

Epiugatric Pulsations

Alcholic

S1

Thyroid

S2

Family History

Added sounds

DM

Murmur

HT

RS

CAD

Breath Sounds

Past History

Added Sounds

DM

Abdomen

TIA

(64)

ECHO CARDIOGRAPHY DIASTOLIC FUNCTION INDICES

IVRT Mitral E m/s A m/s E/A

Tricuspid E m/s A m/s E/A

Deceleration Time (DT)

SYSTOLIC FUNCTION INDICES

IVS d LVPW d LVID d

IVS s LVPW s LVID s

EF % LV Mass

Valves

Mitral Tricuspid

Aortic

RETINOPATHY

MICROALBUMINURIA

CT SCAN

(65)

MASTER CHART

Sl.No GROUP SEX AGE DURATION EF% LV MASS DECE.TIME IVRI E/A

PE TYPE

1 I

2

55

1

56

72.28

240 110 0.635 104

A

2 I

2

40

3

58.3

69.81

140 107 0.721 100

A

3 I

1

60

3

66

107.33

246

142

0.9

76 A

4 I

1

60

5

66

61.61

242 139 0.88

92 A

5 I

1

40

1

55

64.86

178 110 1.54

76 A

6 I

1

59

3

63

124.4

150 110 1.16

80 A

7 I

2

50

1

64

71.76

135

82

1.11

80 A

8 I

2

45

1

50

104.16

241 98 0.823 108

A

9 I

2

58

4

52

80.98

245 99 0.789 90

A

10 I

2

55

4

55

112.19

244 133 0.783 90

A

11 I

2

48

1.5

60

81.92

121

89

1.11

92 A

12 I

2

46

1

56

96.96

167 110 1.13

80 A

13 I

1

40

4

57

68.09

160

78 1.68 110

A

14 I

1

55

4.5

59

59.63

247 139 0.623 78

A

15 I

1

40

1

62

62.12

146 130 1.261 86

A

16 I

1

51

3

64

102

138

87

1.11

78 A

17 I

1

55

4

63

94.21

245 112 0.86

76 A

18 I

2

58

5

58

110.21

241 117 0.58 110

A

19 I

2

42

2

76

92.11

160

86

1.12

80 A

(66)

21 II

2

42

8

73

54

149

75

85

90 A

22 II

1

45

6

72

132.4

242

110

0.8

98 A

23 II

1

60

7

75

65.5

230 117 0.68

82 A

24 II

1

42

6

69

135.4

248

100

1

80 A

25 II

2

50

6

55

89.88

206

92

1.17

78 A

26 II

1

60

8

59

84

244 153 0.66 112

A

27 II

1

60

9

62

126.6

242 105 0.605 80

A

28 II

1

57

6

55

108

180

16

1.22

80 A

29 II

1

50

6

74

102

120

90 1.14 110

A

30 II

2

45

7

50

115.4

241

126

0.9

90 A

31 II

2

45

9

77

64.45

230 125 0.779 82

A

32 II

2

56

6

66

71.48

246 111 0.793 90

A

33 II

2

40

6

52

113.52

244 139 0.75

92 A

34 II

2

40

8

64

116.26

203

71 1.16 110

A

35 II

2

52

9

54

141.66

245

135

0.5

112 A

36 II

2

41

7

58

78

132

82

0.9

80 A

37 II

2

55

7

51

153

244

112

0.8

96 A

38 II

2

42

8

77

63.85

160

89

1.75

82 A

39 II

1

45

9

50

60.84

224

61

1.1

68 A

40 II

1

47

8

60

100

210

80

1.2

75 A

41 III

1

50

16

50

133.36

121

53

1.16

80 A

42 III

2

42

11

71

123.42

242 114 0.631 100

A

(67)